Efficacy and Safety of COVID-19 Vaccines: a Systematic Review and Meta-Analysis of Randomized Clinical Trials

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Review Efﬁcacy and Safety of COVID-19 Vaccines: A Systematic Review and Meta-Analysis of Randomized Clinical Trials

Ali Pormohammad 1, Mohammad Zarei 2, Saied Ghorbani 3 , Mehdi Mohammadi 1 , Mohammad Hossein Razizadeh 3 , Diana L. Turner 4 and Raymond J. Turner 1,*

1 Department of Biological Sciences, University of Calgary, Calgary, AB T2N 1N4, Canada; [email protected] (A.P.); [email protected] (M.M.) 2 John B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; [email protected] 3 Department of Virology, Faculty of Medicine, Iran University of Medical Science, Tehran 1449614535, Iran; [email protected] (S.G.); [email protected] (M.H.R.) 4 Department of Family Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada; [email protected] * Correspondence: [email protected]; Tel.: +1-(403)-220-4308

Abstract: The current study systematically reviewed, summarized and meta-analyzed the clinical features of the vaccines in clinical trials to provide a better estimate of their efﬁcacy, side effects and immunogenicity. All relevant publications were systematically searched and collected from major

Citation: Pormohammad, A.; Zarei, databases up to 12 March 2021. A total of 25 RCTs (123 datasets), 58,889 cases that received the M.; Ghorbani, S.; Mohammadi, M.; COVID-19 vaccine and 46,638 controls who received placebo were included in the meta-analysis. In Razizadeh, M.H.; Turner, D.L.; Turner, total, mRNA-based and adenovirus-vectored COVID-19 vaccines had 94.6% (95% CI 0.936–0.954) R.J. Efficacy and Safety of COVID-19 and 80.2% (95% CI 0.56–0.93) efficacy in phase II/III RCTs, respectively. Efficacy of the adenovirus- Vaccines: A Systematic Review and vectored vaccine after the first (97.6%; 95% CI 0.939–0.997) and second (98.2%; 95% CI 0.980–0.984) Meta-Analysis of Randomized doses was the highest against receptor-binding domain (RBD) antigen after 3 weeks of injections. Clinical Trials. Vaccines 2021, 9, 467. The mRNA-based vaccines had the highest level of side effects reported except for diarrhea and https://doi.org/10.3390/ arthralgia. Aluminum-adjuvanted vaccines had the lowest systemic and local side effects between vaccines9050467 vaccines’ adjuvant or without adjuvant, except for injection site redness. The adenovirus-vectored and mRNA-based vaccines for COVID-19 showed the highest efficacy after first and second doses, Academic Editors: Soo-Hong Lee, Hansoo Park, Jagathesh respectively. The mRNA-based vaccines had higher side effects. Remarkably few experienced Chandra Rajendran and extreme adverse effects and all stimulated robust immune responses. K.S. Jaganathan Keywords: COVID-19; SARS-CoV-2; vaccines; efficacy; side effect; randomized clinical trial; meta-analysis Received: 5 April 2021 Accepted: 28 April 2021 Published: 6 May 2021 1. Introduction Publisher’s Note: MDPI stays neutral Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a non-segmented with regard to jurisdictional claims in positive-sense, single-stranded ribonucleic acid (RNA) beta coronavirus [1] that was first published maps and institutional affil- reported in Wuhan, China. The SARS-CoV-2 infection causes the coronavirus disease 2019 iations. (COVID-19) that became a global pandemic and public health crisis. Over 140 million infected and 3 million deaths are reported from COVID-19 by April 2021, with the death rate accelerating; according to WHO, the case fatality ratio (CFR) of SARS-CoV-2 ranges from less than 0.1% to over 25% depending on the country [2]. Copyright: © 2021 by the authors. To overcome this pandemic, vaccination is the hope for a safe and effective way to Licensee MDPI, Basel, Switzerland. help build protection and reduce disease spread [3]. More than 200 COVID-19 vaccine This article is an open access article candidates presented in different stages of development and over 50 candidates have distributed under the terms and reached clinical trials to date [4], including: Oxford-AstraZeneca’s ChAdOx1/AZD1222, conditions of the Creative Commons Moderna’s mRNA-1273, Pfizer-BioNTech’s mRNA BNT162b2, Gamaleya’s Sputnik V, Attribution (CC BY) license (https:// Johnson & Johnson’s INJ-7843735/Ad26.COV2.s, CoronaVac, Sinopharm’s BBIBP-CorV, creativecommons.org/licenses/by/ Novavax’s NVX-CoV2373, EpiVacCorona, CanSino’s Convidicea (Ad5-nCoV), SinoVac’s 4.0/).

Vaccines 2021, 9, 467. https://doi.org/10.3390/vaccines9050467 https://www.mdpi.com/journal/vaccines Vaccines 2021, 9, 467 2 of 21

CoronaVac, Anhui Zhifei Longcom’s ZF2001, GlaxoSmithKline and Medicago’s CoVLP, and Bharat Biotech’s BBV152/Covaxin. Different strategies have been considered for the development of vaccines against SARS-CoV-2 based on the following vaccine platforms: (I) Nucleic acid mRNA-based vaccines are the newest generation of vaccine production approach [5]. The mRNA vaccine technology is a single-stranded RNA molecule that carries a portion of the coding sequence for the peptide or protein from the virus that can be synthesized in the cytoplasm (ribosomes). The resulting antigen triggers an immune response, including the production of antibodies [5]. For instance, the current vaccines developed by the companies Pfizer and Moderna utilize synthetic mRNA encoding the sequence of the coronavirus’s signature spike protein (S-protein) that is then encapsulated within a lipid vesicle nanoparticle. (II) Vi- ral vector vaccines that are developed with new biotechnology [6]. A modified existing virus, able to infect human cells, is introduced carrying the genetic code of the target virus antigen in order to stimulate an immune response. Oxford-AstraZeneca, Gamaleya, CanSio and Johnson & Johnson developed their vaccines based on a DNA sequence encoding the S-protein inserted into the genome of a modified safe adenovirus. (III) Whole-Pathogen Inactivated virus vaccines consisting of killed/inactivated whole viruses or virus fragments. Here the pathogen’s genetic material is destroyed by heat, chemicals, or radiation, so that they cannot replicate but their presence can still stimulate immunogenicity [7]. Sinopharm, SinoVac, and Bharat Biotech’s vaccines were produced by inactivating the SARS-CoV-2 with B-propiolactone, but all the viral protein remains intact. (IV) Subunit vaccines that contain a fragment of the pathogen, either a protein (Pro-subunit), a polysaccharide, or a combination of both, without introducing viable pathogen particles [8]. Lack of genetic material makes them safe and non-infectious/non-viable. Novavax and Anhui Zhifei Longcom applied this technology for the development of their vaccine, using nanoparti- cles coated with synthetic S-protein and an adjuvant for boosting the immune response. Virus-like particle (VLP) vaccines, also a subunit vaccine, mimic the native virus structure, but contain no viral genetic material [9]. A VLP presents the antigen inserted on a nanoparticle surface. GlaxoSmithKline and Medicago used a plant-derived platform to produce a particle that elicits neutralizing antibody and immune cell (e.g., TH1 T cell) responses against COVID-19. The structural proteins of SARS-CoV-2 include four major proteins: spike (S), membrane (M), and envelope (E) part of the viral surface envelope, and the nucleocapsid (N) protein in the ribonucleoprotien core. Among viral surface elements, the S-protein is a primary target for vaccines and therapeutic development against COVID-19 due to its role in the receptor recognition for cell entry and cell membrane fusion process. The trimeric S-protein contains two subunits, S1 and S2. The S1 contains a receptor-binding domain (RBD), which is responsible for recognizing and binding to the host receptor angiotensin- converting enzyme 2 (ACE2), while the S2 mediates the membrane fusion process by forming a six-helical bundle (6-HB) via the two-heptad repeat (HR) regions [10]. However, S1 is the immunodominant antigen during CoV infections and induces long-lasting and broad-spectrum neutralizing antibodies (NAbs) and T-cell immune responses against the RBD. Thus, the S-protein and the RBD serve as the promising targets of SARS-CoV-2 vaccines and the predominant antigenic target for developing a vaccine [11]. Other antigenic targets, such as non-structural proteins (nsp) 3, nsp8-10 [12], papain-like proteases (PL- pro), and cysteine-like protease (3CLpro) [13] can be considered an alternative for vaccine development, but these are expected to elicit less of an immune response. Efficacy and safety, thus side effect profiles, are core vaccine competencies required by medical care systems and public health. To the best of our knowledge, there is still no comprehensive comparative study around the efficacy and safety of COVID-19-related vaccines. In this regard, we provide here a meta-analysis on available randomized clinical trial (RCT) publications providing information on the efficacy and side effects of COVID-19 vaccines. Vaccines 2021, 9, 467 3 of 21

2. Methods 2.1. Search Strategy The Preferred Reporting Items for Systematic Reviews and Meta-Analyses State- ment (PRISMA) recommendations were followed in this analysis [14]. We searched all clinical trial publications related to SARS-CoV-2 vaccines from the following databases: Scopus, EMBASE, Medline (via PubMed), and Web of Science. All studies published up to 12 March 2021 were searched without language restriction by three independent reviewers. Search medical subject headings (MeSH) terms used were “Covid-19 Vaccine”, “SARS-CoV-2 Vaccine”, “clinical trial” or “phase trial”, and “randomized”, as well as all synonyms. We used the Center for Disease Control (CDC), World Health Organization (WHO), and Google Scholar databases/academic search engines to look for unpublished and grey literature. References and citation lists of selected articles and reviews were also reviewed for any other relevant literature (forward and backward citation, recommended by Cochrane). Additional search strategy details are provided in Table S1.

2.2. Study Selection The records were ﬁrst reviewed by three independent authors based on the title and abstract (MHR, AP, and SG), all unrelated publications were removed and the full texts of the remaining articles were reviewed. Then, two independent reviewers (AP and SG) judged potentially eligible articles and disagreements were resolved by discussion and for each article a consensus was reached.

2.3. Eligibility and Inclusion Criteria The following predetermined conditions had to be met for studies to be considered for inclusion in this meta-analysis. For initial screening, all clinical studies were included in the systematic review, while RCT studies in phase I/II/III of COVID-19 vaccines were included in the meta-analysis.

2.4. Exclusion Criteria Non-randomized studies, studies without a placebo group, preclinical studies, studies on animal phase, meta-analyses, letters to the editor, review articles, studies with no extractable data, and news reports were excluded for the meta-analysis. However, non- randomized studies were included only in the systematic review. Additionally, 11 vaccine studies (43 datasets) with no report in the type of adjuvants were excluded from the adjuvant side effect sub-group meta-analysis.

2.5. Data Extraction Four independent reviewers extracted data from the studies that were chosen. The following data were obtained from each article: ﬁrst authors, trial initiation date, published year, vaccine name, company, study type, vaccine type, adjuvant, store temperature, trial phase, doses, injection interval (days), concentration, volume, trial country, all side effects, and efﬁcacy-related data. Three of the authors (S.G, M.H.R, and A.P) extracted data independently, and another author (M.Z) reviewed extracted data at random; discrepancies were resolved by consensus.

2.6. Quality Assessment The JADAD scale (Oxford quality scoring system) for reporting quality of RCTs was used to evaluate the included articles’ quality. The JADAD scale included the three quality parameters of randomization, blinding, and account of all patients. Two questions are asked for the ﬁrst two parameters, and one question is asked for the third parameter. Each query is given a score of one or zero. The highest acceptable score on the prepared checklist was ﬁve, with the lowest acceptable score being three. Data were derived from papers with a ranking of at least three (Table S2). Vaccines 2021, 9, x FOR PEER REVIEW 4 of 23

query is given a score of one or zero. The highest acceptable score on the prepared checklist was five, with the lowest acceptable score being three. Data were derived from papers Vaccines 2021, 9, 467 with a ranking of at least three (Table S2). 4 of 21

2.7. Analysis 2.7. Analysis Initially, cleaning data and preparing them for analysis was done in Microsoft Office 365 and Initially,analysis cleaningwas performed data and by preparing Comprehensive them for Meta-Analysis analysis was Software done in Microsoft Version 2.0 Office software.365 and The analysis point estimates was performed of the byeffect Comprehensive size, odds ratios Meta-Analysis (ORs), and Software 95% confidence Version 2.0 software. The point estimates of the effect size, odds ratios (ORs), and 95% confidence interval (95% CI) were calculated for estimating vaccine efficacy and side effects. Random interval (95% CI) were calculated for estimating vaccine efficacy and side effects. Random effects models were used to estimate pooled effects. Additionally, to search for heteroge- effects models were used to estimate pooled effects. Additionally, to search for heterogene- neity between studies, the I2 statistic was used [15] and high heterogeneity was character- ity between studies, the I2 statistic was used [15] and high heterogeneity was characterized ized as an I2 > 50%, with sources of heterogeneity established through meta-regression as an I2 > 50%, with sources of heterogeneity established through meta-regression and and subgroup analyses. Subgroup analysis based on the vaccine phases significantly de- subgroup analyses. Subgroup analysis based on the vaccine phases significantly decreased creased the heterogeneity in the high heterogeneity cases. The presence and effect of pub- the heterogeneity in the high heterogeneity cases. The presence and effect of publication lication bias were examined using funnel plots, Begg’s test, and Egger weighted regres- bias were examined using funnel plots, Begg’s test, and Egger weighted regression meth- sion methods [16,17]. For all analyses, two-tailed statistics and a significance level of less ods [16,17]. For all analyses, two-tailed statistics and a significance level of less than 0.05 than 0.05 were considered. were considered.

3. Result3. Result 3.1. 3.1.Characteristics Characteristics of Included of Included Studies Studies A totalA total of 32,790 of 32,790 publications publications were were screen screeneded for forthe theCOVID-19 COVID-19 vaccines’ vaccines’ side side effects effects andand efficacies. efﬁcacies. Out of Out these of studies, these studies, 27 met 27the met systematic the systematic review’s review’sinclusion inclusion criteria (non- criteria randomized(non-randomized and randomized), and randomized), while 25 random while 25ized randomized studies were studies included were in included the meta- in the analysismeta-analysis (Figure 1). (Figure Characteristics1). Characteristics of the se oflected the selected articles articlesare summarized are summarized in Table in 1.Table A 1 . totalA of total 25 studies of 25 studies (123 datasets) (123 datasets) were wereincluded included in the in meta-analysis. the meta-analysis. Studies Studies with with different different vaccinevaccine phase phase reports, reports, number number of ofdoses, doses, inje injectionction concentration, concentration, different different case, case, and and con- control trol groupgroup numbersnumbers are considered considered a a separate separate dataset dataset for for the the meta-analysis. meta-analysis. All Allincluded included studiesstudies were were written written in English. in English. Out of Out 25 of randomized 25 randomized studies, studies, 12 were 12 weredouble-blind, double-blind, 2 participant-blind,2 participant-blind, 6 observer-blind, 6 observer-blind, 3 single-b 3 single-blind,lind, and 2 andpartially 2 partially blind. blind.The number The number of studiesof studies by vaccine by vaccine platforms platforms were 7 were mRNA-based, 7 mRNA-based, 4 pro-subunit, 4 pro-subunit, 8 adenovirus-vector, 8 adenovirus-vector, 5 inactivated,5 inactivated, and 1 and VLPs. 1 VLPs.

FigureFigure 1. Flow 1. Flow diagram diagram of literature of literature search search and and study study selection selection for for meta-analysis meta-analysis (PRISMA (PRISMA flow chart). chart).

Vaccines 2021, 9, 467 5 of 21

Table 1. Characterization of included studies.

Pub. Store Temp RCT Dose Age Range Injection Study Trial Initiation Date Vaccine Name Company Study Type Vaccine Type Adjuvant Concentration Trial Country Ref Year (◦C) Phase (s) (Year) Interval (Days)

Anhui Zhifei Aluminum Yang et al. 22 June and 3 July 2020 2020 ZF2001 Randomized, double-blind, placebo-controlled Pro-Subunit 2–8 I 3 22.9–54.7 30 25 µg * China [18] Longcom hydroxide Anhui Zhifei Aluminum Yang et al. 22 June and 3 July 2020 2020 ZF2001 Randomized, double-blind, placebo-controlled Pro-Subunit 2–8 I 3 20.9–49.4 30 50 µg * China [18] Longcom hydroxide BBV152 Ella et al. 13 and 30 July 2020 2021 Bharat Biotech Randomized, double-blind, placebo-controlled Inactivated Algel-IMDG 2–8 I 2 18–55 14 3 µg * India [19] (Covaxin) BBV152 Ella et al. 13 and 30 July 2020 2021 Bharat Biotech Randomized, double-blind, placebo-controlled Inactivated Algel-IMDG 2–8 I 2 18–55 14 6 µg * India [19] (Covaxin) BBV152 Ella et al. 13 and 30 July 2020 2021 Bharat Biotech Randomized, double-blind, placebo-controlled Inactivated Algel 2–8 I 2 18–55 14 6 µg* India [19] (Covaxin) Adenovirus- Zhu et al. 16 and 27 March 2020 2020 Ad5-nCoV CanSino Non-randomized No adjuvant UN I 1 18–60 No × 10 China [20] based 5 10 VP * Adenovirus- Zhu et al. 16 and 27 March 2020 2020 Ad5-nCoV CanSino Non-randomized No adjuvant UN I 1 18–60 No × 11 China [20] based 1 10 VP * Adenovirus- Zhu et al. 16 and 27 March 2020 2020 Ad5-nCoV CanSino Non-randomized No adjuvant UN I 1 18–60 No × 11 China [20] based 1.5 10 VP * Richmond et al. 19 June and 23 September 2020 2021 SCB-2019 Clover Randomized, double-blind, placebo-controlled Pro-Subunit No adjuvant 2–8 I 2 20–50 21 3 µg * Australia [21] Richmond et al. 19 June and 23 September 2020 2021 SCB-2019 Clover Randomized, double-blind, placebo-controlled Pro-Subunit AS03 2–8 I 2 24–53 21 3 µg * Australia [21] Richmond et al. 19 June and 23 September 2020 2021 SCB-2019 Clover Randomized, double-blind, placebo-controlled Pro-Subunit AS03 2–8 I 2 55–70 21 3 µg * Australia [21] Richmond et al. 19 June and 23 September 2020 2021 SCB-2019 Clover Randomized, double-blind, placebo-controlled Pro-Subunit CpG/Alum 2–8 I 2 20–53 21 3 µg * Australia [21] Richmond et al. 19 June and 23 September 2020 2021 SCB-2019 Clover Randomized, double-blind, placebo-controlled Pro-Subunit CpG/Alum 2–8 I 2 55–71 21 3 µg * Australia [21] Richmond et al. 19 June and 23 September 2020 2021 SCB-2019 Clover Randomized, double-blind, placebo-controlled Pro-Subunit No adjuvant 2–8 I 2 20–54 21 9 µg * Australia [21] Richmond et al. 19 June and 23 September 2020 2021 SCB-2019 Clover Randomized, double-blind, placebo-controlled Pro-Subunit AS03 2–8 I 2 21–53 21 9 µg * Australia [21] Richmond et al. 19 June and 23 September 2020 2021 SCB-2019 Clover Randomized, double-blind, placebo-controlled Pro-Subunit AS03 2–8 I 2 55–64 21 9 µg * Australia [21] Richmond et al. 19 June and 23 September 2020 2021 SCB-2019 Clover Randomized, double-blind, placebo-controlled Pro-Subunit CpG/Alum 2–8 I 2 19–55 21 9 µg * Australia [21] Richmond et al. 19 June and 23 September 2020 2021 SCB-2019 Clover Randomized, double-blind, placebo-controlled Pro-Subunit CpG/Alum 2–8 I 2 55–67 21 9 µg * Australia [21] Richmond et al. 19 June and 23 September 2020 2021 SCB-2019 Clover Randomized, double-blind, placebo-controlled Pro-Subunit No adjuvant 2–8 I 2 18–49 21 30 µg * Australia [21] Richmond et al. 19 June and 23 September 2020 2021 SCB-2019 Clover Randomized, double-blind, placebo-controlled Pro-Subunit AS03 2–8 I 2 19–47 21 30 µg * Australia [21] Richmond et al. 19 June and 23 September 2020 2021 SCB-2019 Clover Randomized, double-blind, placebo-controlled Pro-Subunit AS03 2–8 I 2 55–63 21 30 µg * Australia [21] Richmond et al. 19 June and 23 September 2020 2021 SCB-2019 Clover Randomized, double-blind, placebo-controlled Pro-Subunit CpG/Alum 2–8 I 2 21–50 21 30 µg * Australia [21] Richmond et al. 19 June and 23 September 2020 2021 SCB-2019 Clover Randomized, double-blind, placebo-controlled Pro-Subunit CpG/Alum 2–8 I 2 55–74 21 30 µg * Australia [21] Kremsner et al. June, 2020 2020 CVnCoV Curevac Randomized, partially blind, placebo-controlled mRNA-based No adjuvant 5 I 2 18–60 28 2 µg * Germany [22] Kremsner et al. June, 2020 2020 CVnCoV Curevac Randomized, partially blind, placebo-controlled mRNA-based No adjuvant 5 I 2 19–59 28 4 µg * Germany [22] Kremsner et al. June, 2020 2020 CVnCoV Curevac Randomized, partially blind, placebo-controlled mRNA-based No adjuvant 5 I 2 20–59 28 6 µg * Germany [22] Kremsner et al. June, 2020 2020 CVnCoV Curevac Randomized, partially blind, placebo-controlled mRNA-based No adjuvant 5 I 2 20–59 28 8 µg * Germany [22] Kremsner et al. June, 2020 2020 CVnCoV Curevac Randomized, partially blind, placebo-controlled mRNA-based No adjuvant 5 I 2 19–59 28 12 µg * Germany [22] Ward et al. July, 2020 2020 CoVLP Medicago Randomized, partially blind VLP No adjuvant 2–8 I 2 18–55 21 3.75 µg * Canada [23] Ward et al. July, 2020 2020 CoVLP Medicago Randomized, partially blind VLP CpG 1018 2–8 I 2 18–55 21 3.75 µg * Canada [23] Ward et al. July, 2020 2020 CoVLP Medicago Randomized, partially blind VLP AS03 2–8 I 2 18–55 21 3.75 µg * Canada [23] Ward et al. July, 2020 2020 CoVLP Medicago Randomized, partially blind VLP No adjuvant 2–8 I 2 18–55 21 7.5 µg * Canada [23] Ward et al. July, 2020 2020 CoVLP Medicago Randomized, partially blind VLP CpG 1018 2–8 I 2 18–55 21 7.5 µg * Canada [23] Ward et al. July, 2020 2020 CoVLP Medicago Randomized, partially blind VLP AS03 2–8 I 2 18–55 21 7.5 µg * Canada [23] Ward et al. July, 2020 2020 CoVLP Medicago Randomized, partially blind VLP No adjuvant 2–8 I 2 18–55 21 15 µg * Canada [23] Ward et al. July, 2020 2020 CoVLP Medicago Randomized, partially blind VLP CpG 1018 2–8 I 2 18–55 21 15 µg * Canada [23] Ward et al. July, 2020 2020 CoVLP Medicago Randomized, partially blind VLP AS03 2–8 I 2 18–55 21 15 µg Canada [23] Jackson et al. 16 March and 14 April 2020 2020 mRNA-1273 Moderna Open-label mRNA-based No adjuvant −20 I 2 18–55 28 25 µg * United States [24] Jackson et al. 16 March and 14 April 2020 2020 mRNA-1273 Moderna Open-label mRNA-based No adjuvant −20 I 2 18–55 28 100 mg * United States [24] Jackson et al. 16 March and 14 April 2020 2020 mRNA-1273 Moderna Open-label mRNA-based No adjuvant −20 I 2 18–55 28 250 mg * United States [24] Anderson et al. 16 April and 12 May 2020 2020 mRNA-1273 Moderna Open-label mRNA-based No adjuvant −20 I 2 56–70 28 25 mg * United States [25] Anderson et al. 16 April and 12 May 2020 2020 mRNA-1273 Moderna Open-label mRNA-based No adjuvant −20 I 2 71≤ 28 25 mg * United States [25] Anderson et al. 16 April and 12 May 2020 2020 mRNA-1273 Moderna Open-label mRNA-based No adjuvant −20 I 2 56–70 28 100 mg * United States [25] Anderson et al. 16 April and 12 May 2020 2020 mRNA-1273 Moderna Open-label mRNA-based No adjuvant −20 I 2 71≤ 28 100 mg * United States [25] Australia, Keech et al. 26 May and 6 June 2020 2020 NVX-CoV2373 Novavax Randomized, observer-blind, placebo-controlled Pro-Subunit No adjuvant 2–8 I 2 18–59 21 25 µg/0.6 ml [26] United States Australia, Keech et al. 26 May and 6 June 2020 2020 NVX-CoV2373 Novavax Randomized, observer-blind, placebo-controlled Pro-Subunit Matrix-M1 2–8 I 2 18–59 21 5 µg/0.6 ml [26] United States Australia, Keech et al. 26 May and 6 June 2020 2020 NVX-CoV2373 Novavax Randomized, observer-blind, placebo-controlled Pro-Subunit Matrix-M1 2–8 I 2 18–59 21 25 µg/0.6 ml [26] United States Australia, Keech et al. 26 May and 6 June 2020 2020 NVX-CoV2373 Novavax Randomized, observer-blind, placebo-controlled Pro-Subunit Matrix-M1 2–8 I 1 18–59 21 25 µg/0.6 ml [26] United States Vaccines 2021, 9, 467 6 of 21

Table 1. Cont.

Sahin et al. 23 April and 22 May 2020 2020 BNT162b1 Pfizer/BioNTech Randomized, single-blind mRNA-based No adjuvant (−60)–(−80) I 2 18–55 21 1 µg * Germany [27] Sahin et al. 23 April and 22 May 2020 2020 BNT162b1 Pfizer/BioNTech Randomized, single-blind mRNA-based No adjuvant (−60)–(−80) I 2 21.4–55.8 21 10 µg * Germany [27] Sahin et al. 23 April and 22 May 2020 2020 BNT162b1 Pfizer/BioNTech Randomized, single-blind mRNA-based No adjuvant (−60)–(−80) I 2 25.1–55 21 30 µg * Germany [27] Sahin et al. 23 April and 22 May 2020 2020 BNT162b1 Pfizer/BioNTech Randomized, single-blind mRNA-based No adjuvant (−60)–(−80) I 2 23.9–54 21 50 µg * Germany [27] Sahin et al. 23 April and 22 May 2020 2020 BNT162b1 Pfizer/BioNTech Randomized, single-blind mRNA-based No adjuvant (−60)–(−80) I 1 19.9–47.8 No 60 µg * Germany [27] United States, Walsh et al. 4 May and 22 June 2020 2020 BNT162b1 Pfizer/BioNTech Randomized, observer-blind, placebo-controlled mRNA-based No adjuvant (−60)–(−80) I 2 20.9–53.2 21 10 µg * [28] Germany United States, Walsh et al. 4 May and 22 June 2020 2020 BNT162b1 Pfizer/BioNTech Randomized, observer-blind, placebo-controlled mRNA-based No adjuvant (−60)–(−80) I 2 18–55 21 10 µg * [28] Germany United States, Walsh et al. 4 May and 22 June 2020 2020 BNT162b1 Pfizer/BioNTech Randomized, observer-blind, placebo-controlled mRNA-based No adjuvant (−60)–(−80) I 2 65–85 21 20 µg * [28] Germany United States, Walsh et al. 4 May and 22 June 2020 2020 BNT162b1 Pfizer/BioNTech Randomized, observer-blind, placebo-controlled mRNA-based No adjuvant (−60)–(−80) I 2 18–55 21 20 µg * [28] Germany United States, Walsh et al. 4 May and 22 June 2020 2020 BNT162b1 Pfizer/BioNTech Randomized, observer-blind, placebo-controlled mRNA-based No adjuvant (−60)–(−80) I 2 65–85 21 30 µg * [28] Germany United States, Walsh et al. 4 May and 22 June 2020 2020 BNT162b1 Pfizer/BioNTech Randomized, observer-blind, placebo-controlled mRNA-based No adjuvant (−60)–(−80) 1 2 18–55 21 30 µg * [28] Germany United States, Walsh et al. 4 May and 22 June 2020 2020 BNT162b2 Pfizer/BioNTech Randomized, observer-blind, placebo-controlled mRNA-based No adjuvant (−60)–(−80) I 2 65–85 21 10 µg * [28] Germany United States, Walsh et al. 4 May and 22 June 2020 2020 BNT162b2 Pfizer/BioNTech Randomized, observer-blind, placebo-controlled mRNA-based No adjuvant (−60)–(−80) I 2 18–55 21 10 µg * [28] Germany United States, Walsh et al. 4 May and 22 June 2020 2020 BNT162b2 Pfizer/BioNTech Randomized, observer-blind, placebo-controlled mRNA-based No adjuvant (−60)–(−80) I 2 65–85 21 20 µg * [28] Germany United States, Walsh et al. 4 May and 22 June 2020 2020 BNT162b2 Pfizer/BioNTech Randomized, observer-blind, placebo-controlled mRNA-based No adjuvant (−60)–(−80) I 2 18–55 21 20 µg * [28] Germany United States, Walsh et al. 4 May and 22 June 2020 2020 BNT162b2 Pfizer/BioNTech Randomized, observer-blind, placebo-controlled mRNA-based No adjuvant (−60)–(−80) I 2 65–85 21 30 µg * [28] Germany United States, Walsh et al. 4 May and 22 June 2020 2020 BNT162b2 Pfizer/BioNTech Randomized, observer-blind, placebo-controlled mRNA-based No adjuvant (−60)–(−80) I 2 18–55 21 30 µg * [28] Germany Aluminum Xia et al. 12 April and 2 May 2020 2020 BBIBP-CorV Sinopharm Randomized, double-blind, placebo controlled Inactivated 2–8 I 3 65–85 28 2.5 µg * China [29] hydroxide Aluminum Xia et al. 12 April and 2 May 2020 2020 BBIBP-CorV Sinopharm Randomized, double-blind, placebo controlled Inactivated 2–8 I 3 18–59 28 5 µg * China [29] hydroxide Aluminum Xia et al. 12 April and 2 May 2020 2020 BBIBP-CorV Sinopharm Randomized, double-blind, placebo controlled Inactivated 2–8 I 3 18–59 28 10 µg * China [29] hydroxide Aluminum Xia et al. 29 April and 28 June 2020 2020 BBIBP-CorV Sinopharm Randomized, double-blind, placebo controlled Inactivated 2–8 I 2 18–59 28 2 µg * China [30] hydroxide Aluminum Xia et al. 29 April and 28 June 2020 2020 BBIBP-CorV Sinopharm Randomized, double-blind, placebo controlled Inactivated 2–8 I 2 18–59 28 2 µg * China [30] hydroxide Aluminum Xia et al. 29 April and 28 June 2020 2020 BBIBP-CorV Sinopharm Randomized, double-blind, placebo controlled Inactivated 2–8 I 2 60 ≤ 28 4 µg * China [30] hydroxide Aluminum Xia et al. 29 April and 28 June 2020 2020 BBIBP-CorV Sinopharm Randomized, double-blind, placebo controlled Inactivated 2–8 I 2 18–59 28 4 µg * China [30] hydroxide Aluminum Xia et al. 29 April and 28 June 2020 2020 BBIBP-CorV Sinopharm Randomized, double-blind, placebo controlled Inactivated 2–8 I 2 60 ≤ 28 8 µg * China [30] hydroxide Aluminum Xia et al. 29 April and 28 June 2020 2020 BBIBP-CorV Sinopharm Randomized, double-blind, placebo controlled Inactivated 2–8 I 2 18–59 28 8 µg * China [30] hydroxide Aluminum Zhang et al. 16 and 25 April 2020 2020 CoronaVac Sinovac Randomized, double-blind, placebo controlled Inactivated 2–8 I 2 60≤ 14 3 µg * China [31] hydroxide Aluminum Zhang et al. 16 and 25 April 2020 2020 CoronaVac Sinovac Randomized, double-blind, placebo controlled Inactivated 2–8 I 2 18–59 28 3 µg * China [31] hydroxide Aluminum Zhang et al. 16 and 25 April 2020 2020 CoronaVac Sinovac Randomized, double-blind, placebo controlled Inactivated 2–8 I 2 18–59 14 6 µg * China [31] hydroxide Aluminum Zhang et al. 16 and 25 April 2020 2020 CoronaVac Sinovac Randomized, double-blind, placebo controlled Inactivated 2–8 I 2 18–59 28 6 µg * China [31] hydroxide Adenovirus- Logunov et al. 18 June and 3 August 2020 2020 Sputnik V Gamaleya Non-randomized No adjuvant 2–8 I 1 18–59 No 11 Russia [32] based 10 VP * Adenovirus- Logunov et al. 18 June and 3 August 2020 2020 Sputnik V Gamaleya Non-randomized No adjuvant 2–8 I 1 18–60 No 11 Russia [32] based 10 * Vaccines 2021, 9, 467 7 of 21

Table 1. Cont.

Adenovirus- Logunov et al. 18 June and 3 August 2020 2020 Sputnik V (Lyo) Gamaleya Non-randomized No adjuvant 2–8 I 1 18–60 No 11 Russia [32] based 10 * Adenovirus- Logunov et al. 18 June and 3 August 2020 2020 Sputnik V (Lyo) Gamaleya Non-randomized No adjuvant 2–8 I 1 18–60 No 11 Russia [32] based 10 * Randomized, participant-blind, Adenovirus- United Folegatti et al. 23 April and 21 May 2020 2020 AZD1222 Oxford/AstraZeneca No adjuvant 2–8 I/II 2 18–60 28 × 10 [33] placebo-controlled based 5 10 VP * Kingdom Mulligan et al. 4 May and 19 June 2020 2020 BNT162b1 Pfizer/BioNTech Randomized, observer-blind, placebo-controlled mRNA-based No adjuvant (−60)–(−80) I/II 2 18–55 21 10 µg * Multicenter 1 [34] Mulligan et al. 4 May and 19 June,2020 2020 BNT162b1 Pfizer/BioNTech Randomized, observer-blind, placebo-controlled mRNA-based No adjuvant (−60)–(−80) I/II 2 24–42 21 30 µg * Multicenter 1 [34] Mulligan et al. 4 May and 19 June 2020 2020 BNT162b1 Pfizer/BioNTech Randomized, observer-blind, placebo-controlled mRNA-based No adjuvant (−60)–(−80) I/II 1 23–52 No 100 µg * Multicenter 1 [34] Anhui Zhifei Aluminum Yang et al. 12 and 17 July 2020 2020 ZF2001 Randomized, double-blind, placebo-controlled Pro-Subunit 2–8 II 2 25–53 30 25 µg * China [18] Longcom hydroxide Anhui Zhifei Aluminum Yang et al. 12 and 17 July 2021 2020 ZF2001 Randomized, double-blind, placebo-controlled Pro-Subunit 2–8 II 2 18.8–58.4 30 50 µg * China [18] Longcom hydroxide Anhui Zhifei Aluminum Yang et al. 12 and 17 July 2022 2020 ZF2001 Randomized, double-blind, placebo-controlled Pro-Subunit 2–8 II 3 19.9–59.1 30 25 µg * China [18] Longcom hydroxide Anhui Zhifei Aluminum Yang et al. 12 and 17 July 2023 2020 ZF2001 Randomized, double-blind, placebo-controlled Pro-Subunit 2–8 II 3 20–59.7 30 50 µg * China [18] Longcom hydroxide Adenovirus- Zhu et al. 11 and 16 April 2020 2020 Ad5-nCoV CanSino Randomized, double-blind, placebo-controlled No adjuvant UN II 1 19.3–59.6 No × 11 China [35] based 1 10 * Adenovirus- Zhu et al. 11 and 16 April 2020 2020 Ad5-nCoV CanSino Randomized, double-blind, placebo-controlled No adjuvant UN II 1 18≤ No × 10 China [35] based 5 10 * Chu et al. 29 May and 8 July 2020 2020 mRNA-1273 Moderna Randomized, observer-blind, placebo-controlled mRNA-based No adjuvant −20 II 2 18≤ 28 50 mg * United States [36] Chu et al. 29 May and 8 July 2020 2020 mRNA-1273 Moderna Randomized, observer-blind, placebo-controlled mRNA-based No adjuvant −20 II 2 18–54.99 28 50 mg * United States [36] Chu et al. 29 May and 8 July 2020 2020 mRNA-1273 Moderna Randomized, observer-blind, placebo-controlled mRNA-based No adjuvant −20 II 2 55≤ 28 100 mg * United States [36] Chu et al. 29 May and 8 July 2020 2020 mRNA-1273 Moderna Randomized, observer-blind, placebo-controlled mRNA-based No adjuvant −20 II 2 18–54.99 28 100 mg * United States [36] Randomized, participant-blind, Adenovirus- United Ramasamy et al. 30 May and 8 August 2020 2020 AZD1222 Oxford/AstraZeneca No adjuvant 2–8 II 2 55≤ 28 × 10 [37] placebo-controlled based 2.2 10 VP * Kingdom Randomized, participant-blind, Adenovirus- United Ramasamy et al. 30 May and 8 August 2020 2020 AZD1222 Oxford/AstraZeneca No adjuvant 2–8 II 1 18–55 No × 10 [37] placebo-controlled based 2.2 10 VP * Kingdom Randomized, participant-blind, Adenovirus- United Ramasamy et al. 30 May and 8 August 2020 2020 AZD1222 Oxford/AstraZeneca No adjuvant 2–8 II 2 56–69 28 × 10 [37] placebo-controlled based 2.2 10 VP * Kingdom Randomized, participant-blind, Adenovirus- United Ramasamy et al. 30 May and 8 August 2020 2020 AZD1222 Oxford/AstraZeneca No adjuvant 2–8 II 1 56–69 No × 10 [37] placebo-controlled based 2.2 10 VP * Kingdom Randomized, participant-blind, Adenovirus- United Ramasamy et al. 30 May and 8 August 2020 2020 AZD1222 Oxford/AstraZeneca No adjuvant 2–8 II 2 70≤ 28 × 10 [37] placebo-controlled based 2.2 10 VP * Kingdom Randomized, participant-blind, Adenovirus- 3.5–6.5 × 1010 United Ramasamy et al. 30 May and 8 August 2020 2020 AZD1222 Oxford/AstraZeneca No adjuvant 2–8 II 2 70≤ 28 [37] placebo-controlled based VP * Kingdom Randomized, participant-blind, Adenovirus- 3.5–6.5 × 1010 United Ramasamy et al. 30 May and 8 August 2020 2020 AZD1222 Oxford/AstraZeneca No adjuvant 2–8 II 1 18–55 No [37] placebo-controlled based VP * Kingdom Randomized, participant-blind, Adenovirus- 3.5–6.5 × 1010 United Ramasamy et al. 30 May and 8 August 2020 2020 AZD1222 Oxford/AstraZeneca No adjuvant 2–8 II 2 56–69 28 [37] placebo-controlled based VP * Kingdom Randomized, participant-blind, Adenovirus- 3.5–6.5 ×1010 United Ramasamy et al. 30 May and 8 August 2020 2020 AZD1222 Oxford/AstraZeneca No adjuvant 2–8 II 1 56–69 No [37] placebo-controlled based VP * Kingdom Randomized, participant-blind, Adenovirus- 3.5–6.5 × 1010 United Ramasamy et al. 30 May and 8 August 2020 2020 AZD1222 Oxford/AstraZeneca No adjuvant 2–8 II 2 70≤ 28 [37] placebo-controlled based VP * Kingdom Aluminum Xia et al. 12 April and 2 May 2020 2020 BBIBP-CorV Sinopharm Randomized, double-blind, placebo controlled Inactivated 2–8 II 3 70≤ 28 5 µg * China [29] hydroxide Aluminum Xia et al. 12 April and 2 May 2020 2020 BBIBP-CorV Sinopharm Randomized, double-blind, placebo controlled Inactivated 2–8 II 3 18–59 28 5 µg * China [29] hydroxide Aluminum Xia et al. 18 May and 30 July 2020 2020 BBIBP-CorV Sinopharm Randomized, double-blind, placebo controlled Inactivated 2–8 II 1 18–59 No 8 µg * China [30] hydroxide Aluminum Xia et al. 18 May and 30 July 2020 2020 BBIBP-CorV Sinopharm Randomized, double-blind, placebo controlled Inactivated 2–8 II 2 18–59 14 4 µg * China [30] hydroxide Aluminum Xia et al. 18 May and 30 July 2020 2020 BBIBP-CorV Sinopharm Randomized, double-blind, placebo controlled Inactivated 2–8 II 2 18–59 21 4 µg * China [30] hydroxide Aluminum Xia et al. 18 May and 30 July 2020 2020 BBIBP-CorV Sinopharm Randomized, double-blind, placebo controlled Inactivated 2–8 II 2 18–59 28 4 µg * China [30] hydroxide Aluminum Zhang et al. 3 and 5 May 2020 2020 CoronaVac Sinovac Randomized, double-blind, placebo controlled Inactivated 2–8 II 2 18–59 14 3 µg * China [31] hydroxide Vaccines 2021, 9, 467 8 of 21

Table 1. Cont.

Store Temp RCT Dose Age Range Injection Study Trial Initiation Date Pub. Year Vaccine Name Company Study Type Vaccine Type Adjuvant Concentration Trial Country Ref (◦C) Phase (s) (Year) Interval (Days)

Aluminum Zhang et al. 3 and 5 May 2020 2020 CoronaVac Sinovac Randomized, double-blind, placebo controlled Inactivated 2–8 II 2 18–59 28 3 µg * China [31] hydroxide Aluminum Zhang et al. 3 and 5 May 2020 2020 CoronaVac Sinovac Randomized, double-blind, placebo controlled Inactivated 2–8 II 2 18–59 14 6 µg * China [31] hydroxide Aluminum Zhang et al. 3 and 5 May 2020 2020 CoronaVac Sinovac Randomized, double-blind, placebo controlled Inactivated 2–8 II 2 18–59 28 6 µg * China [31] hydroxide Adenovirus- Logunov et al. 18 June and 3 August 2020 2020 Sputnik V Gamaleya Non-randomized No adjuvant 2–8 II 2 18–59 21 11 Russia [32] based 10 VP * Sputnik V Adenovirus- Logunov et al. 18 June and 3 August 2020 2020 Gamaleya Non-randomized No adjuvant 2–8 II 2 18–60 21 11 Russia [32] (lyophilised) based 10 VP * × 10 Adenovirus- 2.2 10 VP * United Voysey et al. 23 April and 4 November 2020 2021 AZD1222 Oxford/AstraZeneca Randomized, single-blind, placebo-controlled No adjuvant 2–8 II/III 2 18–60 28 × 10 [38] based (1st)/5 10 Kingdom VP * (2nd) Adenovirus- United Voysey et al. 23 April and 4 November 2020 2021 AZD1222 Oxford/AstraZeneca Randomized, single-blind, placebo-controlled No adjuvant 2–8 II/III 2 18≤ 28 × 10 [38] based 5 10 VP * Kingdom Pollack et al. 27 July and 14 November 2020 2020 BNT162b2 Pﬁzer/BioNTech Randomized, observer-blind, placebo-controlled mRNA-based No adjuvant (−60)–(−80) II/III 2 18≤ 21 30 µg/0.3 ml Multinational 1 [39] Baden et al. 27 July and 23 October 2020 mRNA-1273 Moderna Randomized, observer-blind, placebo-controlled mRNA-based No adjuvant −20 III 2 16–89 28 100 µg * United States [40] Adenovirus- Voysey et al. 23 April and 4 November 2020 2021 AZD1222 Oxford/AstraZeneca Randomized, single-blind, placebo-controlled No adjuvant 2–8 III 2 18–95 28 × 10 Brazil [38] based 5 10 VP * 7 September and 24 Adenovirus- Logunov et al. 2021 Sputnik V Gamaleya Randomized, double-blind, placebo controlled No adjuvant 2–8 III 2 18≤ 21 11 Russia [41] November 2020 based 10 VP * Johnson & Adenoviral Sadoff et al. 20 July 2020 2021 Ad26.COV2.S Randomized, double-blind, placebo-controlled No adjuvant UN I/II 2 18–55 No × 10 Belgium, US [42] Johnson vector 5 10 Johnson & Adenoviral Sadoff et al. 20 July 2020 2021 Ad26.COV2.S Randomized, double-blind, placebo-controlled No adjuvant UN I/II 2 19–55 No × 11 Belgium, US [42] Johnson vector 1 10 Johnson & Adenoviral Sadoff et al. November 2020 2021 Ad26.COV2.S Randomized, double-blind, placebo-controlled No adjuvant UN I/II 2 65–83 No × 10 Belgium, US [42] Johnson vector 5 10 Johnson & Adenoviral Sadoff et al. November 2020 2021 Ad26.COV2.S Randomized, double-blind, placebo-controlled No adjuvant UN I/II 2 65–88 No × 11 Belgium, US [42] Johnson vector 1 10 1 From 152 sites worldwide (United States, 130 sites; Argentina, 1; Brazil, 2; South Africa, 4; Germany, 6; and Turkey, 9). UN = unavailable. VP = virus particle; Pro-Subunit = protein subunit; VLP = virus-like particle; Alum = aluminium; Adv= adenovirus; CpG = cytosine-guanine oligodeoxynucleotide; AS03= squalene-based immunologic adjuvant; Algel-IMDG (an imidazoquinoline molecule chemisorbed on alum [Algel]); RCT = randomized control trial. * per 0.5 m. Studies with different reports for the vaccine phase, the vaccine dose, injection concentration, different case, and control group numbers are considered as a separate dataset. More detailed information is provided in Table S3. Vaccines 2021, 9, 467 9 of 21

3.2. Characteristics of Participants A total of 58,889 cases that received the COVID-19 vaccine and 46,638 controls who received placebo were included in this study. Out of 58,889 vaccine cases, 31,070 were male and 27,819 female. Out of 46,638 individuals in the placebo group, 33,354 were male and 13,284 female. All vaccines and placebos were intramuscularly (IM) injected. Detailed information of age ranges of either vaccine or placebo groups is shown in Table1.

3.3. Efficacy of Different COVID-19 Vaccines 3.3.1. Efficacy of mRNA-Based COVID-19 Vaccines The mRNA-based COVID-19 vaccines had 94.6% (95% CI 0.936–0.954) efficacy in a total of 34,041 cases in phase II/III RCTs (Table2). Figure2 shows the efficacy of COVID-19 vaccines after the first and second doses. Efficacy four weeks after first dose was reported for only one antibody (NAb 70.2% (95% CI 0.655–0.746)). Efficacy after a second dose of mRNA-based COVID-19 vaccines was reported for RBD, S-protein, and NAbs, with the highest efficacy for NAbs at 99.5% (95% CI 0.980–0.999) (Table3).

Table 2. Efﬁcacy of adenovirus-based and mRNA-based COVID-19 vaccines.

Number 95% CI (%) Included Heterogeneity Vaccine Type RCT Phase Efﬁcacy (%) Studies Lower Limit Upper Limit Case N Test, p-Value Adenovirus-based 2/3 4 80.2 0.564 0.927 20771 <0.001 mRNA-based 2/3 2 94.6 0.936 0.954 34041 <0.001 RCT = randomized control trial.

3.3.2. Efficacy of Adenovirus-Vectored COVID-19 Vaccines The pooling of four RCTs (in phases II/III) results (a total of 20,771 cases included) showed adenovirus-vectored COVID-19 vaccines had 80.2% (95% CI 0.56–0.93) efficacy (Table2). After the first dose, the efficacy of the adenovirus-vectored COVID-19 vaccine was the highest at 97.6% (95% CI 0.939–0.997) against RBD three weeks after injection. Whereas, adenovirus-vectored COVID-19 vaccine had the highest efficacy by producing NAbs 99.9% (95% CI 0.985–1.000) after 4 and 2 weeks of the second injection (Table3).

3.3.3. Efficacy of Inactivated COVID-19 Vaccines After the first vaccine dose, the inactivated COVID-19 vaccine’s efficacy was the highest against RBD at 91.3% (95% CI 00.564–0.96) four weeks after injection. Whereas, the highest efficacy against S-protein was 94% (95% CI 0.941 0.877–0.973) two weeks after the second injection (Table3).

3.3.4. Efficacy of Pro-Subunit COVID-19 Vaccines Pro-subunit vaccine efficacy was the highest against RBD at 87.3% (95% CI 0.671–0.892) four weeks after the first dose. Similarly, it had the highest efficacy against RBD protein at 95.6% (95% CI 0.937–0.970) four weeks after the second dose (Table3).

3.3.5. Efficacy of VLP COVID-19 Vaccines Efficacy of VLP vaccines was reported only against RBD three weeks after the first dose at 23.8% (95% CI 0.091–0.375) and three weeks after the second dose at 78.7% (95% CI 0.581–0.908) (Table3).

3.4. Side Effects of Different COVID-19 Vaccines Adjusted pooled odds ratio (OR) between vaccine and placebo groups were assessed for estimating the association of side effects by the administration of different COVID-19 vaccines. mRNA-based vaccines had the highest number of associated side effects, except for diarrhea and arthralgia, for which the adenovirus-vectored vaccine had the highest OR (Figure3). Vaccines 2021, 9, x FOR PEER REVIEW 11 of 23

3.3. Efficacy of Different COVID-19 Vaccines 3.3.1. Efficacy of mRNA-Based COVID-19 Vaccines The mRNA-based COVID-19 vaccines had 94.6% (95% CI 0.936–0.954) efficacy in a total of 34,041 cases in phase II/III RCTs (Table 2). Figure 2 shows the efficacy of COVID- 19 vaccines after the first and second doses. Efficacy four weeks after first dose was reported for only one antibody (NAb 70.2% (95% CI 0.655–0.746)). Efficacy after a second dose of mRNA-based COVID-19 vaccines was reported for RBD, S-protein, and NAbs, with the highest efficacy for NAbs at 99.5% (95% CI 0.980–0.999) (Table 3).

Table 2. Efficacy of adenovirus-based and mRNA-based COVID-19 vaccines.

95% CI (%) Heterogeneity Test, Vaccine Type RCT Phase Number Studies Efficacy (%) Included Case N Lower Limit Upper Limit p-Value Adenovirus-based 2/3 4 80.2 0.564 0.927 20771 <0.001 mRNA-based 2/3 2 94.6 0.936 0.954 34041 <0.001 RCT = randomized control trial. Vaccines 2021, 9, 467 10 of 21

Vaccines 2021, 9, x FOR PEER REVIEW 12 of 23

(a)

(b) FigureFigure 2. Efﬁcacy 2. Efficacy of differentof different COVID-19 COVID-19 vaccines (a () aafter) after the thefirst ﬁrstand ( andb) second (b) second doses. doses.

Table 3. Efficacy of different COVID-19 vaccines after the first and second doses. The administration of mRNA-based vaccine was associated with a greater number

of side effects, such as injectionVaccine site pain, fever, redness, swelling,Placebo induration, pruritus, Antigen/An- After Injec- Studies Lower Upper Studies Lower Upper Shot Vaccine Type Efficacy I-Squared Efficacy I-Squared tibody tion (Week)chills, myalgia,N arthralgia,Limit vomiting, Limit fatigue, andN headache,Limit by yieldingLimit a summary OR Adenovirus- of 83.06 (95% CI4 37.05–186.1)0.603 0.471 (in phase0.722 II/III 73.8 RCTs), 2 36.900.004 (95%0.001 CI 12.34–105.21)0.027 0 (in phase 2 based I/II/IIIInactivated RCTs), 24.40 4 0.870 (95% CI0.734 18.73–31.77) 0.983 (in 93.8 phase 4 I/II/III0.024 RCTs),0.008 18.790.072 (95% 0 CI 4.87–72.40) (inAdenovirus- phase I/II/III RCTs), 17.5 (95% CI 1.96–155.58) (in phase I/II RCTs), 17.50 (95% CI 2 0.976 0.939 0.997 0.0 NA NA NA NA NA 3 based RBD 1.98–155.58) (in phase II/III RCTs), 13.11 (95% CI 7.19–23.89) (in phase II/III RCTs), 10.71 VLP 8 0.238 0.091 0.375 84.3 NA NA NA NA NA (95%Adenovirus- CI 6.51–17.60) (in phase I/II RCTs), 9.67 (95% CI 1.27–76.90) (in phase III/II RCTs), 2 0.966 0.942 0.980 0.0 2 0.004 0.001 0.027 0 8.71 (95%based CI 4.38–17.34) (in phase I/II RCTs), 6.16 (95% CI 5.86–6.48) (in phase III RCTs), 4 andInactivated 5.13 (95% CI 4 2.32–11.31)0.913 0.564 (in phase0.958 I/II 90.7 RCTs), 4 respectively,0.061 0.033 compared0.110 to 0 other types Pro-Subunit 6 0.628 0.590 0.665 0.0 NA NA NA NA NA 2 of vaccines. Inactivated Nevertheless, 2 0.293 0.182 the adenovirus-vectored0.437 0.0 2 0.083 vaccine 0.032 was associated0.202 0 with higher 3 rates Pro-Subunit of diarrhea 4 with0.790 OR 0.474 of 4.59 0.874 (95% CI 91.0 3.58–5.89), 4 0.021 and arthralgia0.005 0.079 OR of 010.61 (95% CI

After 1st dose S-protein Inactivated 2 0.396 0.269 0.539 0.0 2 0.021 0.003 0.134 0 4 7.60–14.83) compared to others (Table4). It should be considered that heterogeneity (I- Pro-Subunit 4 0.873 0.671 0.892 91.9 4 0.021 0.005 0.079 0 2 squared Inactivated test) of 4 the0.583 pooled 0.210 meta-analysis 0.868 95.0 for most 4 of0.030 the side0.013 effects 0.070 was low 0 (I2 < 50%), 3 which Pro-Subunit indicates 4 that0.551 variation 0.291 in study0.786 outcomes 85.0 4 between0.021 the0.005 included0.079 studies 0 was low, Adenovirus- NAb even though different2 0.547 companies0.496 0.596 and different 76.8 2 research0.008 groups0.002 across0.031 the 0 world have based 4 beenInactivated included. 4 More 0.691 detailed 0.537 information0.812 95.0 such as 4 Forest0.025 plot,0.008 Funnel 0.074 plot, 0heterogeneity test,mRNA-based and sub-group 4 0.702 analysis 0.655 of each0.746 side 73.9 effects 4 are0.010 shown 0.004 in Figures0.026 S1–S21 0 (in the Inactivated 9 0.929 0.876 0.960 61.8 9 0.171 0.077 0.336 85 2 Supplementary Materials). mRNA-based 5 0.731 0.532 0.866 86.0 NA NA NA NA NA Adenovirus- 3 0.982 0.980 0.984 0.0 1 0.149 0.139 0.159 0 RBD 3 based VLP 9 0.787 0.581 0.908 78.1 NA NA NA NA NA Inactivated 4 0.944 0.842 0.982 15.9 4 0.063 0.026 0.143 0 4 Pro-Subunit 6 0.956 0.937 0.970 0.0 NA NA NA NA NA Inactivated 7 0.941 0.877 0.973 61.4 7 0.290 0.139 0.507 87 2 Pro-Subunit 18 0.852 0.719 0.928 62.4 18 0.028 0.014 0.052 0

After 2nd dose S-protein mRNA-based 5 0.786 0.725 0.836 0.0 NA NA NA NA NA Inactivated 4 0.934 0.842 0.974 15.9 4 0.063 0.026 0.143 0 4 Pro-Subunit 14 0.792 0.679 0.873 50.7 15 0.031 0.015 0.061 0 Adenovirus- 1 0.999 0.985 1.000 0.0 NA NA NA NA NA NAbs 2 based Inactivated 9 0.845 0.724 0.919 86.5 9 0.151 0.068 0.303 85

Vaccines 2021, 9, 467 11 of 21

Table 3. Efﬁcacy of different COVID-19 vaccines after the ﬁrst and second doses.

Vaccine Placebo Antigen/ After Injection Shot Vaccine Type Studies N Efﬁcacy Lower Limit Upper Limit I-Squared Studies N Efﬁcacy Lower Limit Upper Limit I-Squared Antibody (Week) Adenovirus-based 4 0.603 0.471 0.722 73.8 2 0.004 0.001 0.027 0 2 Inactivated 4 0.870 0.734 0.983 93.8 4 0.024 0.008 0.072 0 Adenovirus-based 2 0.976 0.939 0.997 0.0 NA NA NA NA NA 3 RBD VLP 8 0.238 0.091 0.375 84.3 NA NA NA NA NA Adenovirus-based 2 0.966 0.942 0.980 0.0 2 0.004 0.001 0.027 0 4 Inactivated 4 0.913 0.564 0.958 90.7 4 0.061 0.033 0.110 0 Pro-Subunit 6 0.628 0.590 0.665 0.0 NA NA NA NA NA After 1st dose 2 Inactivated 2 0.293 0.182 0.437 0.0 2 0.083 0.032 0.202 0 3 Pro-Subunit 4 0.790 0.474 0.874 91.0 4 0.021 0.005 0.079 0 S-protein Inactivated 2 0.396 0.269 0.539 0.0 2 0.021 0.003 0.134 0 4 Pro-Subunit 4 0.873 0.671 0.892 91.9 4 0.021 0.005 0.079 0 2 Inactivated 4 0.583 0.210 0.868 95.0 4 0.030 0.013 0.070 0 3 Pro-Subunit 4 0.551 0.291 0.786 85.0 4 0.021 0.005 0.079 0 NAb Adenovirus-based 2 0.547 0.496 0.596 76.8 2 0.008 0.002 0.031 0 4 Inactivated 4 0.691 0.537 0.812 95.0 4 0.025 0.008 0.074 0 mRNA-based 4 0.702 0.655 0.746 73.9 4 0.010 0.004 0.026 0 Inactivated 9 0.929 0.876 0.960 61.8 9 0.171 0.077 0.336 85 2 mRNA-based 5 0.731 0.532 0.866 86.0 NA NA NA NA NA Adenovirus-based 3 0.982 0.980 0.984 0.0 1 0.149 0.139 0.159 0 RBD 3 VLP 9 0.787 0.581 0.908 78.1 NA NA NA NA NA Inactivated 4 0.944 0.842 0.982 15.9 4 0.063 0.026 0.143 0 4 Pro-Subunit 6 0.956 0.937 0.970 0.0 NA NA NA NA NA Inactivated 7 0.941 0.877 0.973 61.4 7 0.290 0.139 0.507 87 2 Pro-Subunit 18 0.852 0.719 0.928 62.4 18 0.028 0.014 0.052 0 S-protein mRNA-based 5 0.786 0.725 0.836 0.0 NA NA NA NA NA After 2nd dose Inactivated 4 0.934 0.842 0.974 15.9 4 0.063 0.026 0.143 0 4 Pro-Subunit 14 0.792 0.679 0.873 50.7 15 0.031 0.015 0.061 0 Adenovirus-based 1 0.999 0.985 1.000 0.0 NA NA NA NA NA Inactivated 9 0.845 0.724 0.919 86.5 9 0.151 0.068 0.303 85 2 Pro-Subunit 23 0.753 0.667 0.823 68.2 19 0.028 0.015 0.052 0 mRNA-based 9 0.870 0.747 0.938 82.4 4 0.008 0.003 0.024 0 NAbs 3 Adenovirus-based 1 0.958 0.955 0.961 0.0 1 0.071 0.065 0.079 0 Adenovirus-based 1 0.999 0.985 1.000 0.0 NA NA NA NA NA Inactivated 4 0.700 0.375 0.901 86.1 4 0.033 0.011 0.099 0 4 Pro-Subunit 17 0.759 0.574 0.881 62.9 15 0.031 0.015 0.061 0 mRNA-based 4 0.995 0.980 0.999 0.0 4 0.016 0.007 0.035 0 S-protein = spike protein, Alum = aluminium, CpG = cytosine-guanine oligodeoxynucleotide, AS03 = squalene-based immunologic adjuvant, RBD = receptor-binding domain, NAb = neutralizing antibody, Pro-Subunit = protein subunit, NA = not available. Vaccines 2021, 9, 467 12 of 21

Vaccines 2021, 9, x FOR PEER REVIEW 14 of 23

FigureFigure 3. 3Local. Local and and systemic systemic side side effects effects of of different different COVID-19 COVID-19 vaccines.vaccines.

Table 4. AssociationThe administration of side effects of mRNA-based with different vaccine COVID-19 was vaccines. associated with a greater number of side effects, such as injection site pain, fever, redness, swelling, induration, pruritus, chills, myalgia, arthralgia, vomiting, fatigue,Odds and Ratio headache, by yielding a summaryHeterogeneity OR of 83.06 Side Effect Vaccine Type Phase Included Study (95% CI 37.05–186.1) (in phase II/III(95% RCTs), CI) 36.90 (95% CI 12.34–105.21)Test, (in phase I-Squared I/II/III RCTs), 24.40 (95%2/3 CI 18.73–31.77) 83.06 (in (37.05–186.1) phase I/II/III RCTs), 5 18.79 (95% CI 4.87–72.40) 81.33 (in mRNA-based phase I/II/III RCTs),1/2 17.5 (95% 28.26 CI 1.96–155.58) (16.18–49.35) (in phase I/II 17 RCTs), 17.50 (95% 0 CI 1.98– 155.58) (in phase 2/3II/III RCTs), 13.11 13.64 (95% (8.39–22.17) CI 7.19–23.89) (in 2 phase II/III RCTs), 10.71 0 (95% Adenovirus-based CI 6.51–17.60) (in1/2 phase I/II RCTs), 3.2 9.67 (2.7–4) (95% CI 1.27–76.90) 2 (in phase III/II RCTs), 0 8.71 Site pain (95% CI 4.38–17.34) (in phase I/II RCTs), 6.16 (95% CI 5.86–6.48) (in phase III RCTs), and 2/3 1.73 (0.667–4.5) 6 46.64 Inactivated 5.13 (95% CI 2.32–11.31)1/2 (in phase 3.19 I/II (1.3–7.6)RCTs), respectively, compared 10 to other types 52.14 of vaccines. Nevertheless, the adenovirus-vectored vaccine was associated with higher rates of 2/3 2.14 (1.01–4.5) 4 48.55 Pro-Subunitdiarrhea with OR of 4.59 (95% CI 3.58–5.89), and arthralgia OR of 10.61 (95% CI 7.60–14.83) 1/2 2.29 (0.48–10.8) 2 29.93 compared to others (Table 4). It should be considered that heterogeneity (I-squared test) Adenovirus-basedof the pooled meta-analysis 1/2/3 for most 1.21 (0.77–1.89)of the side effects was 2low (I2 < 50%), which 0 indicates Inactivated 1/2/3 0.402 (0.056–2.90) 2 0 Swelling that variation in study outcomes between the included studies was low, even though dif- Pro-Subunit 1/2/3 6.48 (3.09–13.67) 5 0 mRNA-basedferent companies 1/2/3 and different 18.79 research (4.87–72.40) groups across the 3 world have been 59.08 included. More detailed information such as Forest plot, Funnel plot, heterogeneity test, and sub- Adenovirus-based 1/2/3 1.35 (0.815–2.25) 4 0 group analysis of each side effects are shown in Figures S1–S21 (in the Supplementary Redness Pro-Subunit 1/2/3 7.29 (3.70–14.38) 6 0 mRNA-basedMaterials). 1/2/3 24.40 (18.73–31.77) 1 0

Adenovirus-based 1/2 3.10 (1.96–4.89) 1 0 Itch Inactivated 1/2 0.32 (0.02–5.3) 1 0 Pro-Subunit 1/2 25.44 (7.85–82.40) 6 0

Vaccines 2021, 9, 467 13 of 21

Table 4. Cont.

Odds Ratio Heterogeneity Side Effect Vaccine Type Phase Included Study (95% CI) Test, I-Squared Cough Adenovirus-based 1/2/3 1.76 (1.20–2.58) 3 0 Adenovirus-based 1/2/3 1.73 (0.57–5.66) 3 90.5 Inactivated 1/2/3 0.27 (0.09–0.76) 5 0 Fever Pro-Subunit 1/2/3 1.17 (0.73–1.86) 4 0 mRNA-based 1/2/3 36.90 (12.34–105.21) 3 43.31 3 4.63 (4.4–4.86) 1 0 mRNA-based 2 2.32 (1.28–4.19) 4 69.20 1/2 5.13 (2.32–11.31) 5 63.02 2 2.54 (1.65–3.91) 2 0 Headache Adenovirus-based 1/2 3.01 (2.35–3.87) 1 0 3 0.58 (0.49–0.68) 1 0 Inactivated 2 0.18 (0.02–1.14) 2 0 2 1.25 (0.33–4.7) 2 0 Pro-Subunit 1/2 1.99 (1.21–3.26) 14 0 Adenovirus-based 1/2 2.72 (2.2–3.37) 3 0 Inactivated 1/2 0.39 (0.18–0.82) 7 0 Pro-Subunit 1/2 2.7 (1.01–7.16) 4 37.2 Fatigue 1/2 5.0 (3.42–7.33) 24 48.23 mRNA-based 2–3 4.87 (4.65–5.09) 1 0 3 6.16 (5.86–6.48) 1 0 Adenovirus-based 1/2 0.16 (0.05–0.49) 2 46.44 Inactivated 1/2 0.18 (0.06–0.58) 4 0 Induration Pro-Subunit 1/2 2.62 (1.23–5.58) 2 0 mRNA-based 1/2 17.5 (1.96–155.58) 1 0 Adenovirus-based 1/2 2.75 (1.99–3.82) 3 0 Inactivated 1/2 0.32 (0.02–5.38) 1 0 Vomiting 1/2 8.71 (4.38–17.34) 8 0 mRNA-based 2–3 4.87 (4.65–5.09) 1 0 3 6.16 (5.86–6.48) 1 0 Adenovirus-based 1/2 2.51 (1.12–5.63) 2 0 Diarrhea Inactivated 1/2 0.60 (0.13–2.83) 3 0 mRNA-based 1/2 0.54 (0.27–1.10) 5 0 Adenovirus-based 1/2 4.59 (3.58–5.89) 3 0 Inactivated 1/2 1.43 (0.25–8.08) 2 0 Pro-Subunit 2.92 (0.57–8.75) 8 53.30 Myalgia 1/2 10.71 (6.51–17.60) 10 33.74 mRNA-based 2/3 7.0 (6.57–7.47) 1 0 3 1.43 (0.25–8.08) 1 0 Adenovirus-based 2/3 4.06 (2.99–5.57) 3 0 Arthralgia Pro-Subunit 2/3 1.34 (0.47–3.83) 4 4.833 mRNA-based 2/3 9.67 (1.27–76.90) 3 67.97 Adenovirus-based 2/3 10.61 (7.60–14.83) 1 0 Chills mRNA-based 2/3 13.11 (7.19–23.89) 8 3.82 Adenovirus-based 2/3 0.54 (0.23–1.25) 2 0 Pruritus mRNA-based 2/3 17.50 (1.98–155.58) 1 0 Vaccines 2021, 9, 467 14 of 21

Serious Adverse Side Effects of COVID-19 Vaccines Only three studies reported anaphylactic shock as an adverse effect of COVID-19 vaccines—(1) 1 out of 84 vaccine cases for the inactivated vaccine [30]; (2) 1 case out of 2063 vaccinated for the adenovirus-based vaccine [38], (3) 1 case out of 15,181 in the vaccine group, and 1 case out of 15,170 in the placebo group, for the mRNA-based vaccine [40]. A total of 37 blot clots, including 22 pulmonary embolus cases (PE) and 5 deep vein thrombosis (DVT), have been reported for the Oxford-AstraZeneca vaccine among 17 million people in the EU and Britain [43]; see discussion for recent contributions. The number of

Vaccines 2021, 9, x FOR PEER REVIEWclotting events is not greater than what is seen in the general population, with no indication17 of 23 that there is a causal effect.

3.5. Side Effects of COVID-19 Vaccines Based on Different Adjuvants CpG/AlumThe sub-group 2/3 analysis 2.42 was (0.13–44.50) assessed to estimate 1 the potential side effects 0 of COVID-19 vaccinesMatrix-M1 based on2/3 the different 1.57 types(0.26–9.4) of administrated 3 adjuvants. Interestingly, 67.96 in all cases, potassiumNo adjuvant aluminum 2/3 sulfate 9.66 (alum)(3.97–23.47) had the smallest 8 number of systemic 49.99 and local side Alum 2/3 0.608 (0.13–2.87) 3 0 Diarrhea effects compared to other adjuvants or vaccines without adjuvant, except injection site redness,No adjuvant of which 2/3 vaccines 0.89without (0.40–1.97) adjuvant had higher 6 rates of site redness 50.47 (Figure 4). Ac- Alum 2/3 2.40 (1.51–3.83) 22 44.55 Injection site pain cordingly, vaccines with alum adjuvant had lower systemic side effects of fatigue OR 0.392 (95%No adjuvant 0.18–0.82), vomiting 2/3 25.61 0.325 (13.31–49.30) (95% 0.02–5.30), fever 7 0.85 (95% 0.51–1.43), 36.60 myalgia 1.43 Itch Alum 2/3 13.20 (3.23–53.90) 7 40.58 Local (95% 0.25–8.0), diarrhea 0.608 (95% 0.13–2.87), and injection site pain 2.40 (95% 1.51–3.83) Swelling betweenAlum different2/3 adjuvants 3.83 and (1.52–9.64) vaccines with no 7 adjuvant (Table5). The 37.52 vaccine with Alum 2/3 7.29 (3.7–14.39) 6 0 Redness no adjuvant was associated with higher redness OR 0.923 (95% 0.23–3.6). Itch OR 13.20 (95%No adjuvant 3.23–53.90 ) and 2/3 swelling 0.923 OR (0.23–3.6) of 3.83 (95% 1.52–9.64) 2 was only reported 0 for vaccines Alum = aluminum, CpGwith = cytosine-guanine alum adjuvant. oligodeoxynucleotide, For more detailed AS03 information = squalene-based see Figures immunologic S22–S30. adjuvant.

Figure 4. Association of adjuvant side effects of different COVID-19 vaccines. Figure 4. Association of adjuvant side effects of different COVID-19 vaccines.

Vaccines 2021, 9, 467 15 of 21

Table 5. Side effects of COVID-19 vaccines based on different adjuvant types.

Odds Ratio (95% Included Heterogeneity Side Effect Adjuvant Type Phase CI) Study Test, I-Squared Alum 2/3 0.392 (0.18–0.82) 7 0 Fatigue Matrix-M1 2/3 3.70 (1.36–10.02) 3 24.81 No adjuvant 2/3 4.43 (2.62–7.49) 6 54.08 Alum 2/3 0.325 (0.02–5.30) 1 0 Vomiting No adjuvant 2/3 3.46 (1.45–8.26) 7 0 Alum 2/3 0.85 (0.51–1.43) 9 20.78 Systemic Fever No adjuvant 2/3 2.96 (1.22–7.17) 2 68.19 Alum 2/3 1.43 (0.25–8.0) 2 0 AS03 2/3 14.331 (3.39–60.56) 3 0 Myalgia CpG/Alum 2/3 2.42 (0.13–44.50) 1 0 Matrix-M1 2/3 1.57 (0.26–9.4) 3 67.96 No adjuvant 2/3 9.66 (3.97–23.47) 8 49.99 Alum 2/3 0.608 (0.13–2.87) 3 0 Diarrhea No adjuvant 2/3 0.89 (0.40–1.97) 6 50.47 Alum 2/3 2.40 (1.51–3.83) 22 44.55 Injection site pain No adjuvant 2/3 25.61 (13.31–49.30) 7 36.60 Itch Alum 2/3 13.20 (3.23–53.90) 7 40.58 Local Swelling Alum 2/3 3.83 (1.52–9.64) 7 37.52 Alum 2/3 7.29 (3.7–14.39) 6 0 Redness No adjuvant 2/3 0.923 (0.23–3.6) 2 0 Alum = aluminum, CpG = cytosine-guanine oligodeoxynucleotide, AS03 = squalene-based immunologic adjuvant.

4. Discussion The purpose of vaccination is to protect individuals from infection and transmission. Although the emergency use authorization for some of the COVID-19 vaccines has been approved by the Food and Drug Administration in the US and the Department of Health and Human Services of each country, the vaccines’ efficacy and side effects have not yet been comprehensively discussed, although popular media and politicians have made many unsubstantiated claims. Therefore, in the current meta-analysis, we provide systematic and comprehensive data regarding the vaccines’ safety, efficacy, and immunogenicity against SARS-CoV-2. Here, we mainly focused on available RCTs publications on the safety, efficacy, and immunogenicity of COVID-19 vaccines. The present study was carefully surveyed for the general and specific target antigen efficacy of each vaccine group. Our analysis showed that variation in the efficacy of vaccines after the first doses are remarkable in comparison with the efficacies after the second doses. Therefore, enrollment of the second dose should produce a more reliable outcome and efficacy compared to a single dose. In total, mRNA-based COVID-19 vaccines had 94.6% efficacy. The RNA-based vaccine elicited high levels of NAbs after one month of the first (70%) and second (99.5%) doses. Unfortunately, data for the RNA-based vaccines against RBD antigen were not available after the first dose. Protection against variants has been shown with the mRNA-based vaccine against the United Kingdom (B.1.1.7, also called 20I/501Y.V1) variant [44,45], but they may be less effective against the variant first detected in South Africa (B.1.351, known as 20H/501Y.V2) [46]. A week after the second dose of mRNA-based vaccine, induction of neutralizing antibody titers in the serum sample was 6- fold lower for participants bearing B.1.351 variant compared to original Wuhan-Hu-1 spike protein [47]. The B.1.351 variant carries two substitutions within the S-protein, which can escape three classes of therapeutically relevant antibodies. These data indicate reinfection with antigenically distinct variants and mitigates the full efficacy of spike-based COVID-19 vaccines [48]. Vaccines 2021, 9, 467 16 of 21

From our summary analysis, the total efficacy of the adenovirus-vectored COVID-19 vaccines was 80.2%. The highest efficacy after a single dose is reported with the adenovirus- vectored COVID-19 vaccines, with very low variation and CI against RBD at 3 weeks (96.7%) and 4 weeks (96.6%) after vaccination compared to placebo controls. Some of the adenovirus-vectored COVID-19 vaccines, such as Johnson & Johnson, need just one dose, with the efficacy against RBD being a possible reason. However, based on the rollout timeline, long-term (more than four weeks) efficacy of adenovirus-vectored COVID-19 vaccines was not reported by any of the RCTs. For the other vaccine types, total efficacy has not been reported, only the antigen-specific efficacy was reported in these RCTs. The pro-subunit vaccine had the highest efficacy against spike antigen at 1 month after the first injection. The efficacy of the VLP vaccines was lower than other COVID-19 vaccines and reported only against RBD after the first (23.8%) and second dose (78.7%). All reports for VLP vaccines are from RCT phase I trials, and the lower efficacy of these vaccines may be the most probable reason. Any vaccine is expected to cause temporary side effects caused by activation of an immune response and injection site tissue trauma. Uptake of vaccines is related to perceived and real adverse side effects, both short-term and long-term. In this study, adjusted pooled odds ratios between vaccine and placebo groups indicated that RNA-based vaccines had higher rates of side effects in reactogenicity, including site pain, swelling, redness, fever, headache, fatigue, induration, vomiting, myalgia, chills, and pruritus (Table2). No sign of cough or itch was found in RNA-based vaccines, and lower rates of diarrhea and arthralgia were observed for this vaccine. By avoiding negativity bias, this might provide strong evidence of RNA-based vaccines’ effectiveness, by eliciting a more robust immune response than other vaccine groups. Additionally, the rate of serious adverse side effects such as anaphylactic shock, an allergic reaction, was not remarkable with this vaccine, with only one case reported in both the vaccine and placebo groups [40]. In the context of side effects, the adenovirus-vectored vaccines are associated with increased diarrhea and arthralgia in comparison with other vaccines, see Table2. A recent systematic review and meta-analysis by Yuan et al. [49] showed no significant difference in systemic reactions, with only local side effects, including pain, itching, and redness, being reported [49]. One case of anaphylactic shock was reported for this vaccine [38]. Several pulmonary emboli (PE) and deep vein thrombosis (DVT) cases have been reported as rare events for the Oxford-AstraZeneca vaccine, causing a temporary suspension of this vaccine’s use in many countries and age-specific rollout in others. However, to date, the data are too weak and anecdotal to provide clear evidence of cause and effect [50]. Similarly, the Johnson & Johnson vaccine was also temporarily suspended in April 2021 by the FDA, as several people developed rare blood-related problems of thrombosis with thrombocytopenia syndrome leading to cerebral venous sinus thrombosis (CVST) [51]. A DVT has also been reported shortly after the second dose of an mRNA-based vaccine as well [52]. Anaphylaxis as an acute allergic reaction has also been reported as a rare event for some vaccines, such as mRNA COVID-19 vaccines [53] and adenovector vaccines against COVID-19 [54]. Overall, these severe life-threatening adverse events are occurring rarely, thus supporting the ongoing rollout of global vaccination programs. Data are currently emerging on Vaccine-induced Immune Thrombotic Thrombocy- topenia (VITT) following vaccination with COVID-19 vaccines [55]. VITT presents with symptoms of thromboembolism and especially signs of thrombocytopenia, cerebral blood clots, or abdominal or arterial clots, such as easy bruising, bleeding or new and/or severe headaches, and pain in the abdomen or a painful, cold numb extremity, particularly with onset 4 to 28 days after immunization. This is due to thrombosis (blood clots) involving the cerebral venous sinuses, or CVST (large blood vessels in the brain), and other sites in the body (including but not limited to the large blood vessels of the abdomen and the veins of the legs) along with thrombocytopenia, or low blood platelet counts. These events are rare, but to date have been documented for the mRNA vaccines BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna) and the adenoviral vector vaccines ChAdOx1 nCoV-19 vaccine Vaccines 2021, 9, 467 17 of 21

(Astra Zeneca) and Ad26. COV2-S vaccine (Janssen; Johnson & Johnson). Given the very recent emergence, our meta study does not include an analysis of VITT. Co-administration of vaccine with adjuvants is being used in VLP subunit vaccines and certain inactivated vaccines [55]. Adjuvants have an essential role owning to inducing specific immune responses, IgG1, and NAbs titers. It also considers potential dose-sparing of CoV vaccine [56]. Multiple adjuvants, such as alum salts, emulsions, and TLR agonists have been formulated for SARS-CoV, SARS-CoV-2, and MERS-CoV [55]. The potential side effects of COVID-19 vaccines based on the different types of adjuvants investigated showed that alum-adjuvanted CoV vaccines had the lowest systemic side effects among other adjuvants or non-adjuvant in Table3. The non-adjuvanted vaccines revealed im- munopathologic reactions including high fatigue, vomiting, fever, myalgia, and diarrhea and redness, while alum-adjuvanted CoV vaccines showed itch and swelling. Overall, the metadata obtained in this study demonstrated that the alum-adjuvanted CoV vaccines had the smallest number of issues compared with other adjuvants and the non-adjuvant formulations. The limitations of this study are: 1. The overall effectiveness and antigen-specific efficacy of some vaccines have not been reported after the first or second dose. 2. Some trials had considerable bias by not including a sufficient number of samples or a broad enough geographical, economic, and age diversity. 3. Timing of vaccine trials in relation to overall prevalence through the COVID-19 pandemic impacts direct comparison. 4. The IgG and IgM antibodies in serum levels had a wide range of variation across the different vaccines after the first or second dose, thus, these data were not included in the meta- analysis. 5. The lack of data on specific categories of patients such as pregnant patients and lifestyles. 6. All RCTs followed up the vaccine and placebo groups one month after both first and second doses, therefore, all reports are related to short-term impacts of the vaccine. 7. For the prevention of database bias, we searched various databases and websites for finding all relevant and gray publications and a proper test for publication bias using Egger’s regression test conducted. We did not find remarkable publication bias in this study by Egger’s regression test. However, publication bias and heterogeneity for some of the pooled results, as well as all the above limitations, must be considered when interpreting the outcomes.

5. Conclusions The adenovirus-vectored and mRNA-based vaccines for COVID-19 showed the highest efficacy after first and second doses, respectively. The mRNA-based vaccines had higher side effects. Only a rare few recipients have experienced extreme adverse effects and all stimulated robust immune responses. All RCTs followed up the vaccine and placebo groups after one month after both first and second doses, therefore, all reports are related to short-term impacts. Due to the timeline, all the vaccines are missing longer-term assess- ments. This meta-analysis allows us to incorporate relevant new evidence for summarizing and analyzing the clinical features of current vaccines for COVID-19 in phase I, II, and III RCTs. The results support the overall efficacy and safety of all available COVID-19 vaccines, providing clear data-driven evidence to support the ongoing global public health effort to vaccinate the entire population.

Supplementary Materials: The following are available online at https://www.mdpi.com/article/10 .3390/vaccines9050467/s1, Figure S1. Meta-analysis A. Forest plot, B. Funnel plot for the injection site pain as a side effect of different COVID 19 vaccine in phase 2/3 RCT, Figure S2. Meta-analysis A. Forest plot, B. Funnel plot for the injection site pain as a side effect of different COVID 19 vaccine in phase 1/2 RCT, Figure S3. Meta-analysis A. Forest plot, B. Funnel plot for the Swelling as a side effect of different COVID 19 vaccine in phase 1/2/3 RCT, Figure S4. Meta-analysis A. Forest plot, B. Funnel plot for the Redness as a side effect of different COVID 19 vaccine in phase 1/2/3 RCT, Figure S5. Meta-analysis A. Forest plot, B. Funnel plot for the Itch as a side effect of different COVID 19 vaccine in phase 1/2 RCT, Figure S6. Meta-analysis A. Forest plot, B. Funnel plot for the Cough as a side effect of different COVID 19 vaccine in phase 1/2/3 RCT, Figure S7. Meta-analysis A. Forest Vaccines 2021, 9, 467 18 of 21

plot, B. Funnel plot for the Fever as a side effect of different COVID 19 vaccine in phase 1/2/3 RCT, Figure S8. Meta-analysis A. Forest plot, B. Funnel plot for the Headache as a side effect of different COVID 19 vaccine in phase 1/2 RCT, Figure S9. Meta-analysis A. Forest plot, B. Funnel plot for the Headache as a side effect of different COVID 19 vaccine in phase 2 RCT, Figure S10. Meta-analysis A. Forest plot, B. Funnel plot for the Headache as a side effect of different COVID 19 vaccine in phase 3 RCT, Figure S11. Meta-analysis A. Forest plot, B. Funnel plot for the Fatigue as a side effect of different COVID 19 vaccine in phase 1/2 RCT, Figure S12. Meta-analysis A. Forest plot, B. Funnel plot for the Fatigue as a side effect of different COVID 19 vaccine in both mRNA-based vaccine, in RCT 2/3, and 3, Figure S13. Meta-analysis A. Forest plot, B. Funnel plot for the Induration as 1 a side effect of different COVID 19 vaccine in RCT 2 , Figure S14. Meta-analysis A. Forest plot, B. 1 Funnel plot for the Vomiting as a side effect of different COVID 19 vaccine in RCT 2 , Figure S15. Meta-analysis A. Forest plot, B. Funnel plot for the Vomiting as a side effect of different COVID 19 vaccine in both mRNA-based vaccine, in RCT 2/3, and 3, Figure S16. Meta-analysis A. Forest plot, 1 B. Funnel plot for the Diarrhea as a side effect of different COVID 19 vaccine in RCT 2 , Figure S17. Meta-analysis A. Forest plot, B. Funnel plot for the Myalgia as a side effect of different COVID 19 1 vaccine in RCT 2 , Figure S18. Meta-analysis A. Forest plot, B. Funnel plot for the Myalgia as a side effect of different COVID 19 vaccine in RCT 3, Figure S19. Meta-analysis A. Forest plot, B. Funnel plot for the Arthralgia as a side effect of different COVID 19 vaccine in RCT 2/3, Figure S20. Meta-analysis A. Forest plot, B. Funnel plot for the Chills as a side effect of different COVID 19 vaccine in RCT 2/3, Figure S21. Meta-analysis A. Forest plot, B. Funnel plot for the Pruritus as a side effect of different COVID 19 vaccine in RCT 2/3, Figure S22. Meta-analysis A. Forest plot, B. Funnel plot for the Fatigue as a side effect based on the adjuvant type in phase 2/3 RCT, Figure S23. Meta-analysis A. Forest plot, B. Funnel plot for the Diarrhea as a side effect based on the adjuvant type in phase 2/3 RCT, Figure S24. Meta-analysis A. Forest plot, B. Funnel plot for the Injection site pain as a side effect based on the adjuvant type in phase 2/3 RCT, Figure S25. Meta-analysis A. Forest plot, B. Funnel plot for the Itch as a side effect based on the adjuvant type in phase 2/3 RCT, Figure S26. Meta-analysis A. Forest plot, B. Funnel plot for the Myalgia as a side effect based on the adjuvant type in phase 2/3 RCT, Figure S27. Meta-analysis A. Forest plot, B. Funnel plot for the Swelling as a side effect based on the adjuvant type in phase 2/3 RCT, Figure S28. Meta-analysis A. Forest plot, B. Funnel plot for the Redness as a side effect based on the adjuvant type in phase 2/3 RCT, Figure S29. Meta-analysis A. Forest plot, B. Funnel plot for the Vomiting as a side effect based on the adjuvant type in phase 2/3 RCT, Figure S30. Meta-analysis A. Forest plot, B. Funnel plot for the Fever as a side effect based on the adjuvant type in phase 2/3 RCT, Table S1. Search strategy, Table S2. Quality assessment of included studies. Author Contributions: Conceived and designed the study: A.P., S.G. and M.Z.; Comprehensive research: S.G., M.H.R. and A.P.; Analyzed the data: A.P. and R.J.T.; Wrote and revised the paper: A.P., M.Z., S.G., M.M., M.H.R., D.L.T. and R.J.T.; Participated in data analysis and manuscript editing: A.P., M.Z., S.G., M.M., M.H.R. and R.J.T. All authors have read and agreed to the published version of the manuscript. Funding: The author(s) received no specific funding for this work. Institutional Review Board Statement: The manuscript is a systematic review, so ethical approval was not required for the study. Informed Consent Statement: Not applicable. Data Availability Statement: All data needed to evaluate the conclusions in the paper are included and/or available within the Supplementary Materials. Additional data related to this paper may be requested from the authors. Acknowledgments: None. Conflicts of Interest: The authors declare no competing interest. The author(s) declare no competing financial interests. Vaccines 2021, 9, 467 19 of 21

Abbreviations

PRISMA The Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement MeSH Medical subject headings WHO World Health Organization CDC Center for Disease Control RCT Randomized clinical trial COVID-19 Coronavirus disease 2019 alum Potassium aluminum sulfate VLPs Virus-like particles ORs Odds ratios 6-HB six-helical bundle SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2 95% CI 95% conﬁdence interval GMT Geometric mean titer RBD Receptor-binding domain PLpro Papain-like proteases 3CLpro Cysteine-like protease NAb Neutralizing antibody Pro-subunit Protein subunit VLP Virus-like particle BMI Body mass index CFR Case fatality ratio RNA Ribonucleic acid messenger RNA mRNA S-protein Spike protein ACE2 Angiotensin-converting enzyme 2 nsp Non-structural proteins IM Intramuscular

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